Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in the United States with estimated 48,960 new cases and 40,560 deaths in 2015 (Siegel, R. L. et al. CA. Cancer J. Clin. 2015, 65, 5-29). With a five-year overall survival rate of merely 7 percent, PDAC is the most lethal cancer among major malignancies. Its poor prognosis is partly due to the fact that PDAC is usually diagnosed at advanced stages. Moreover, pancreatic cancer cells acquire a large number of genetic mutations and are notoriously resistant to apoptotic cell death, an established cancer cell-killing mechanism elicited by anti-cancer agents (Jones, S. et al. Science 2008, 321, 1801-1806; and Hezel, A. F. et al. Genes Dev. 2006, 20, 1218-1249). Despite numerous efforts, there still is a dire lack of effective therapeutic options for advanced pancreatic cancer (Garrido-Laguna, I. et al. Nat. Rev. Clin. Oncol. 2015, 12, 319-334; and Spadi, R. et al. World J. Clin. Oncol. 2016, 7, 27-43). Modulation of macroautophagy (hereafter referred to as autophagy) has been proposed as a promising strategy (Gomez, V. E. et al. Semin. Cancer Biol. 2015, 35, 11-19).
Autophagy is a conserved cellular process through which cytosolic components, such as proteins and organelles, are sequestered, degraded, and recycled (He, C. et al. Annu. Rev. Genet. 2009, 43, 67-93; and Choi, A. M. et al. N. Engl. J. Med. 2013, 368, 651-662). The precise roles of autophagy in tumorigenesis and cancer therapy still remain to be defined due to the heterogeneous nature of cancers and the complexity of the autophagy machinery (Galluzzi, L. et al. EMBO J. 2015, 34, 856-880). Studies have shown that autophagy plays different or even opposite roles depending on the cancer type and the stage of tumor progression. Currently, it is generally accepted that autophagy behaves as a tumor suppressor in normal cells in part because it removes damaged cellular components. Nevertheless, increasing evidence shows that autophagy is a cytoprotective mechanism often exploited by established cancer cells to cope with their harsh microenvironment and cellular stresses induced by chemotherapies. A number of anticancer agents with diverse mechanisms of action have been shown to induce autophagy (Sui, X. et al. Cell Death Dis. 2013, 4, e838; and Dong, Z. et al. Blood Rev. 2016, doi: 10.1016/j.blre.2016.04.005). More importantly, autophagy inhibitors enhance the efficacy of many anticancer agents (Sui, X. et al. Cell Death Dis. 2013, 4, e838). For pancreatic cancer, it has been shown that autophagy is elevated and required for de novo tumor growth and inhibition of autophagy leads to robust tumor regression (Fujii, S. et al. Cancer Sci. 2008, 99, 1813-1819; and Yang, S. et al. Genes Dev. 2011, 25, 717-729); however, the status of p53, whose mutation is commonly seen in pancreatic cancer patients, may determine the outcome of autophagy inhibition (Rosenfeldt, M. T. et al. Nature 2013, 504, 296-300; and Yang, A. et al. Cancer Discov. 2014, 4, 905-913). Despite the complexity of autophagy inhibition as a therapeutic strategy, these studies suggest that disabling the pro-survival autophagy machinery hijacked by cancer cells might represent a viable approach to promote cell death and reduce drug resistance in refractory cancers such as pancreatic cancer (Gomez, V. E. et al. Semin. Cancer Biol. 2015, 35, 11-19; and Sui, X. et al. Cell Death Dis. 2013, 4, e838).
Therefore, there is a need for new compounds to treat cancer, especially pancreatic cancer.